Tuberculosis has reemerged as one of the leading causes of death, and Mycobacterium tuberculosis (Mtb) is the major etiologic agent of tuberculosis in humans. Another etiologic agent of tuberculosis in humans is Mycobacterium bovis. Also, a tuberculosis-like disease in humans may be caused by so-called atypical mycobacteria, such as but not limited to Mycobacterium avium intracellulare. The major cause of tuberculosis in ecomically important animals such as cattle is Mycobacterium bovis. Mycobacterium tuberculosis infects about one-third of the human population, persists for decades, and causes disease in a small fraction of those infected. Despite the low disease rate, Mycobacterium tuberculosis is the single leading cause of death of humans from bacterial infection and accounts for an extraordinary proportion of the chronic infectious morbidity and mortality of humankind. Resistance to each clinically approved anti-tuberculous drug is widespread among clinical isolates of M. tuberculosis. Thus, chemotherapy directed against new classes of targets is an urgent need.
It is known that Mycobacterium tuberculosis persists for prolonged periods in macrophages, that the host immune system responds to Mycobacterium tuberculosis with both oxidative and nitosative stress, and that Mycobacterium tuberculosis evades these insults. In Mycobacterium tuberculosis, dihydrolipoamide acyltransferase (DlaT; formerly termed succinyl transferase) is a component of the peroxynitrite reductase complex, and encodes one component of pyruvate dehydrogenase (PDH). DlaT has been shown to take part in protecting Mycobacterium tuberculosis from oxidative and nitrosative stress in macrophages. Mutant M. tuberculosis strains lacking DlaT are readily killed by mouse macrophages, and DlaT is necessary for full virulence of M. tuberculosis in mice [Shi and Ehrt, Infection and Immunity 74, 56-63 (2006)]. Compounds that inhibit DlaT or its expression are useful for the treatment of tuberculosis.